The pathophysiology associated with endovascular stent usage is well documented and is observed in up to 50% of all patients receiving the medical device. CD47 is a ubiquitously expressed transmembrane protein, that when bound to its cognate receptor Signal Regulatory Protein alpha (SIRP?), inhibits the immune response. We have shown, both ex vivo and in a rat carotid stent model, that immobilized recombinant CD47, or a 21 amino acid peptide sequence (pepCD47) thereof, significantly inhibited restenosis and thrombosis. The overall objective of the proposed research is to investigate the anti-restenotic capacity of a pepCD47 functionalized endovascular stent in rabbit and porcine animal models.
Three Specific Aims (SA) will test our central hypothesis that immobilized pepCD47 represents a pragmatic surface modification strategy that will control adverse immunological and hemocompatibility responses and thus significantly contribute to biocompatibility of endovascular stents. In SA 1 we will fabricate and perform efficacy and stability analysis on CD47 functionalized metal surface to test our working hypothesis that rabbit and pig CD47, immobilized on the bare metal surfaces, will confer a similar anti-platelet and anti-inflammatory activity as human CD47 and will be amenable to clinically relevant challenges. SA 2 will determine how immobilized CD47 affects cellular interactions at the blood/stent interface. Our working hypothesis is that immobilized CD47 confers a biocompatible microenvironment that inhibits inflammatory cell and platelet interactions and permits re- endothelialization. SA 3 will demonstrate in vivo efficacy of CD47 functionalized stents in the large animal models. Our working hypothesis is that CD47 modified stents would confer significantly greater biocompatibility, compared to commercially available bare metal stents and drug eluting stents (DES), which will be demonstrated by a significant reduction in ISR of the stented site. The rationale for the proposed research is that demonstration of pepCD47 mediated inhibition of ISR in a large animal model would provide necessary preclinical and usage data to advance the application of the CD47-functionalized stents into the clinical realm. The research is significant because it will demonstrate the broad translational importance of CD47 in regulating the cellular/molecular response to synthetic surfaces that are used in clinically relevant biomedical devices. The research proposed herein is innovative because it challenges and redirects current therapeutic strategies, such as DES, by identifying candidate molecular signaling mechanisms that actively regulate cellular interactions with solid synthetic surfaces, and then incorporating these concepts into the design and fabrication of metallic stents.
The proposed research is relevant to public health because it addresses the pathophysiology associated with endovascular stent usage. Specifically, we will investigate a novel approach for addressing the inflammatory and thrombotic response to endovascular stent deployment that involves immobilizing a naturally expressed protein marker of self, CD47, to the metallic stent surface. This project is relative to the NIH?s mission because it will lead to improvements of a widely used medical device.
